goxin has recently been described. The influence of a short or more prolonged course of antibiotics that might indirectly “treat” this normally commensal organism is not understood.
The microbiome is thought to contribute to human metabolism. The most discussed is probably the relationship of the microbiome to risk for obesity. There has been a lot of research looking at the effect of low-dose continuous antibiotic administration (STAT or subtherapeutic antibiotic treatment) and pulse administration (PAT or pulsed antibiotic treatment.) Some of the PAT studies are the most interesting. One study involved PAT (amoxicillin with or without tylosin versus no antibiotic) to female infant mice for three days at ten to fourteen days, at twenty-eight days, and at thirty-seven days of age. Following out to 150 days of life, PAT mice showed more muscle mass than control and increased bone area and mineral content. Interestingly, the microbiota diversity in fecal pellets was permanently decreased out to 150 days, more than 100 days after the last course of antibiotic (800 species in mothers and controls, reduced to 700 after one course of antibiotic, and even further reduced to 200 species if the mice were given tylosin). Not only were there significantly fewer species but the spectrum of species was not as evenly distributed as seen in control mice not given the antibiotic. Epidemiologic studies of children demonstrate that receiving antibiotics within the first six months of life is associated with higher risk of obesity (Avon Longitudinal Study of Parents and Children—ALSPAC—in Britain). Much more work needs to be done to understand and expand this experimental and epidemiologic data. These issues are somewhat illustrated by Dr. Martin J. Blaser’s own professional and personal journey with Helicobacter pylori. The journey is outlined in his book Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues. He is one of the world’s experts on H. pylori as a result of his laboratory and epidemiologic research. H. pylori resides only in the stomach lining and is known to be associated with higher risk for gastric ulcer and gastric cancer. In the absence of any symptoms, he discovered he was H. pylori antibody positive, and positive for the virulence factor CagA protein. In the absence of symptoms, he was treated, under the now mistaken thought that “the only good H. pylori is a dead H. pylori.” Six months after antibiotic treatment, with falling antibody titers and clearing of the organism on repeat gastroscopy, he developed symptoms of gastrointestinal reflux disease (GERD). It is now know that H. pylori may help protect against symptoms of GERD. It is also thought that early colonization in children (but not adults) may help lower the risk of subsequent asthma. Thus H. pylori provides an example of amphibiosis.
Alterations in Fecal Microbiota
Treatment for various conditions associated with alterations in the fecal microbiota is still in its infancy. The most established is fecal microbiota transplantation (FMT) for relapsing Clostridium difficile colitis. This diagnosis has become much more common, related to more widespread use of broad-spectrum antibiotics as well as increased virulence of C. difficile. Although C. difficile is part of the normal flora of the human colon, the production of toxin can lead to severe and life-threatening disease. All treating clinicians are aware of the high risk for disease relapse after an apparently successful initial course of antibiotics for this diagnosis. Fecal transplantation has WWW.SFMS.ORG
been used for more than 100 years in animal husbandry. The benefit of this treatment for recurrent disease in humans has been increasingly recognized over the last five years. However, the mechanism of action is not well understood. Is it related to the microbiota themselves, such as the Firmicutes and Bacteroidetes phyla, or some other aspect such as bile acids or other immunologic or metabolic factors? Development of equally effective commercial (not human-derived) preparations depends on better information. There are examples where apparently successful approaches to disease treatment using immunologic methodology have not be successful. Bovine colostrum was tried for recalcitrant cryptosporidium enteritis in the setting of advanced HIV infection. Despite reports of efficacy in cows, it does not work in humans.
Next Steps in Microbiome Research
The discussion has attempted to suggest some of the problems with and gaps in the current knowledge. These are outlined in the proceedings of the first NIH-sponsored workshop entitled Human Microbiome Science: Vision for the Future, conducted July 23-25, 2013 (http://www.genome.gov/27554404). Despite the immense expansion of knowledge about the microbiota in stool and vaginal flora, there is much more to be developed for a fuller understanding of the impact of and solution to antibiotic-associated changes in the microbiome. Given the rather primitive knowledge at present, are there recommendations that can be made now? I believe the answer is yes. My suggestions include: (1) The development of better diagnostic tools to establish the diagnosis of infection rather than simple colonization; (2) fewer antibiotic courses, eliminating use in clinical situations where antibiotics have shown little impact; (3) shortening the duration of treatment to a course shown to be efficacious (e.g., prolonged course of macrolides has no impact on the chronic cough associated with pertussis); (4) use of an antibiotic with narrowest spectrum of activity (corollary: development of newer antibiotics with more restricted spectra of activity); (5) development of new approaches to treatment that do not involve direct-acting antibiotics (e.g., FMT or more focused immunologic or anti-inflammatory interventions); (6) development and use of better vaccines (e.g., the diphtheria toxin-conjugated pneumococcal vaccine, which appears to decrease spread of pneumococcus); (7) continued promotion of reduction of antibiotic use in animal and poultry husbandry, which the SFMS and CMA have been advocating for more than a decade; and (8) possibly promoting the concept of developing a more robust microbiome early in each infant’s life. Stephen Follansbee, MD, is a retired HIV and infectious diseases specialist in San Francisco. Since completing his postgraduate training at UCSF, he practiced for sixteen years with the Infectious Diseases Associates Medical Group and then another sixteen years with Kaiser Permanente in San Francisco. He is a clinical professor of medicine at UCSF and longtime member and past-president of the SFMS. Since retirement his main activities have been to say “no” to most requests for new responsibilities and to say “yes” to becoming certified in scuba diving. SEPTEMBER 2014 SAN FRANCISCO MEDICINE
San Francisco Medicine, Vol. 87, No. 7, September 2014